Evaluating analgesic efficacy and administration route following craniotomy in mice using the grimace scale

Abstract

Most research laboratories abide by guidelines and mandates set by their research institution regarding the administration of analgesics to control pain during the postoperative period. Unfortunately, measuring pain originating from the head is difficult, making adequate decisions regarding pain control following stereotaxic surgery problematic. In addition, most postsurgical analgesia protocols require multiple injections over several days, which may cause stress and distress during a critical recovery period. Here we sought to 1) assess the degree of postoperative pain following craniotomy in mice, 2) compare the efficacy of three common rodent analgesics (carprofen, meloxicam and buprenorphine) for reducing this pain and 3) determine whether the route of administration (injected or self-administered through the water supply) influenced pain relief post-craniotomy. Using the mouse grimace scale (MGS), we found that injectable analgesics were significantly more effective at relieving post-craniotomy pain, however, both routes of administration decreased pain scores in the first 24 h post-surgery. Specifically, buprenorphine administered independently of administration route was the most effective at reducing MGS scores, however, female mice showed greater sensitivity to carprofen when administered through the water supply. Although it is necessary to provide laboratory animals with analgesics after an invasive procedure, there remains a gap in the literature regarding the degree of craniotomy-related pain in rodents and the efficacy of alternative routes of administration. Our study highlights the limitations of administering drugs through the water supply, even at doses that are considered to be higher than those currently recommended by most research institutions for treating pain of mild to moderate severity.

Differential modulation of thermal preference after sensitization by optogenetic or pharmacological activation of heat-sensitive nociceptors

“…Recent studies have characterized a variety of mouse behaviors that may be more reflective of spontaneous pain and supraspinal processes associated with clinical conditions, including free-choice temperature preference assays. 6,7,9,[12][13][14][15] However, most assays used to assess thermal preference rely on mouse avoidance responses to noxious temperatures rather than assessment of native preference. 7 In contrast, our assay does not necessarily expose mice to noxious temperature ranges and therefore provides a measure of response to innocuous temperature, allowing for a study of thermal allodynia or thermotaxis.…”

“…35,36 Thus, in direct contrast to reflexive responses in acute nociception assays, the preference of a particular temperature is driven by persistent sensory processing and the motivation to move to different temperatures may reflect non-reflexive and integrative sensory processing or coping behavior with important motivational or homeostatic components, such as avoiding pain or discomfort. 37,38 Additionally, given that mice are a prey species that tend to hide overt behavioral signs of pain or distress 12,15 , assays that rely on more subtle behavioral outputs, such as thermal selection, may provide a unique insight into subtle but physiologically relevant changes in sensory preferences and thresholds.…”

“…The mice habituated to the arena itself for 30 minutes before each trial. Experiments were conducted on mice [8][9][10][11][12][13][14][15][16] weeks of age during the light cycle.…”

“…These concerns have led to increased usage of unconditioned or non-evoked behavioral responses with the aim of capturing endogenous indicators of spontaneous or ongoing pain. 11 Such measures include operant assays, the Mouse Grimace Scale 12,13 , and automated behavioral tracking 7 , weight-bearing or gait analysis, nesting or burrowing behavior, ultrasonic vocalizations, and free-choice temperature preference. 14,15 Along with increased adoption of assays for spontaneous pain, there has also been an increase in the automation of data collection.…”

Grimace Scores: Tools to Support the Identification of Pain in Mammals Used in Research

“…Grimace scales have been applied across numerous research models, species and environmental contexts [ 41 , 128 ] ( Table 4 ). They are a technique that can also be used to detect pain in existing pain research models as well as analgesic drug studies [ 40 , 41 , 42 , 45 , 60 , 77 , 109 , 110 , 128 , 129 , 130 ]. Grimace scales offer the ability to detect and assess the severity of pain, determine the potential benefit of any analgesic intervention and assist in identifying humane interventions.…”